Retinoic acid (RA) is a critical signaling molecule in both embryonic development and in post-natal life. RA is the active metabolite of Vitamin A (retinol) and exists in several isoforms, of which all-trans RA (atRA), 13-cisRA and 9,13-dicisRA are those most commonly detected in the human body. Endogenous RA isomers are essential for stem cell and neuronal differentiation, in regulating insulin stimulated glucose secretion, in regulating cell cycles and apoptosis, and in the maintenance of healthy skin, epithelia and the immune system. A high level of cellular atRA has efficient antiproliferatory effects.
The biological activity of the RAs is mainly manifested by their binding to nuclear RA receptors (RARs), which leads to increased transcription of the target genes. The observed effects on gene transcription are thus dependent on cellular concentrations of atRA and on the expression levels of the three RAR isoforms. Catabolism of cellular atRA is achieved by members of the cytochrome P450 family 26 (CYP26), and in particular CYP26A1 in the liver and CYP26B1 in other adult human tissues. Inhibition of members of the CYP26 family may therefore provide a means to ensure elevated levels of endogenous atRA in the cells. Such inhibitors are referred to as retinoic acid metabolism blocking agents, RAMBAs.
A number of indications have been shown to lead to local up-regulation of atRA degrading enzymes and to respond favorably to treatment using exogenous atRA (or one of its isoforms) due to its ability to down-regulate cell proliferation.
These indications include dermatological conditions such as severe acne/rosacea, psoriasis, and keratinocytic ichthyosis. Synthetic vitamin A derivatives (retinoids) have long been the mainstay of treatment for several disorders of keratinization, notably the ichthyoses and severe acne. Some forms of psoriasis also respond well.
In terms of cosmetic anti-aging applications, prescribed creams containing atRA (intended for treatment of acne), are the only preparations with proven effect against fine lines and wrinkles.
Recent studies have shown that retinoic acid protects against intestinal inflammation mainly by shifting the Treg/Th17 profile, allowing for the treatment of inflammatory bowel diseases.
atRA has been successful in the chemotherapy treatment of various cancer forms such as neuroblastoma (NBI), acute promyelocytic leukaemia (APL), prostate cancer and to some extent post-menopausal breast cancer. One of the most impressive effects of atRA has been observed in the treatment of APL. Treatment of patients suffering from APL with high dose of atRA resulted in complete remission. Furthermore, several experiments in animals have demonstrated that atRA inhibited the induction and caused the disappearance of prostate tumors. In spite of these encouraging results, knowledge of the effects of prolonged atRA therapy on human cancers in the clinic has been scarce. It has been suggested that the therapeutic effects of atRA are undermined by its rapid in vivo metabolism and catabolism by cytochrome P450 enzymes (CYPs).
Emerging evidence, both clinical and molecular, indicates that retinoids may also be used to treat atherosclerotic lesions and restenosis phenomena in cardiovascular disease. Although the data from clinical trials examining the effect of vitamin A and vitamin A precursors on cardiac events have been contradictory, these data do suggest that retinoids do influence fundamental processes relevant to atherosclerosis. Preclinical cellular and animal model studies support these concepts. Retinoids exhibit complex effects on proliferation, growth, differentiation and migration of vascular smooth muscle cells (VSMC), including responses to injury and atherosclerosis. Retinoids also appear to exert important inhibitory effects on thrombosis and inflammatory responses relevant to atherogenesis. Recent studies suggest that retinoids may also be involved in vascular calcification and endothelial function, for example, by modulating nitric oxide pathways.
Treatment by addition of exogenous atRA or one of its isoforms is therefore often the main treatment or a co-treatment for these conditions.
Although atRA-treatment as such is a successful treatment modality, excessive intake of Vitamin A leads to a syndrome known as hypervitaminosis A or retinoic acid syndrome, characterized by erythema, weight and hair loss, bone pain, liver problems, build-up of fluid in lungs and in the rest of the body, kidney failure, skin and eye irritations, and teratogenicity. In addition, patients may also develop RA resistance during treatment.
To overcome these severe and unwanted side effects, the use of selective CYP26 inhibitors has been proposed, possibly together with mild addition of exogenous atRA. The most common and well-studied of these RAMBAs are ketoconazole, liarozole and talarozole. Albeit successful to varying degrees in cell tests, animal models, and clinical trials, their efficacy is not extraordinary. The main focus for all three RAMBAs has in this context been to target CYP26A1 for treatment of psoriasis, the rare disease keratinocytic ichthyosis, and prostate cancer.
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The inventors have surprisingly found that the compounds disclosed herein may be useful as inhibitors of CYP26, in particular the CYP26B1 isoform.